The present invention relates to crystalline forms of a potent platelet glycoprotein IIb/IIIa antagonist known as roxifiban. Roxifiban is an acetate salt methyl ester prodrug form of a potent platelet glycoprotein IIb/IIIa antagonist. It is a non-peptide isoxazoline compound represented by the following structural formula: ##STR1##
Roxifiban is known by its chemical name, methyl-N.sup.3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N.sup.2 -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate acetate salt. Roxifiban is encompassed within the description and claims of Patent Cooperation Treaty application number PCT/US94/13155 (International Publication Number WO 95/14683) filed on Nov. 14, 1994, the disclosure of which is incorporated herein by reference. This international patent application claims priority from U.S. Ser. No. 08/157,598, filed Nov. 24 1993, U.S. Ser. No. 08/232,961, filed Apr. 22, 1994 and U.S. Ser. No. 08/337,920, filed Nov. 10, 1994, the disclosure of each of which is incorporated herein by reference. The synthesis of the trifluoroacetic acid salt of the prodrug base of roxifiban is described in Example 314B of PCT/US94/13155.
The active component of roxifiban has been found to inhibit the binding of soluble adhesive proteins, such as fibrinogen, von Willebrand factor, fibronectin and vitronectin, to the platelet glycoprotein IIb/IIIa complex. As a consequence, the compound is capable of inhibiting the activation and aggregation of platelets induced by all known endogenous platelet agonists. roxifiban is, therefore, useful for the treatment or prevention of thromboembolic disorders including thrombosis or embolus formation, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, restenosis, atherosclerlosis, stroke, myocardial infarction and unstable angina. Other diseases that involve cell adhesion processes may also be treated by the administration of roxifiban. Such diseases include, for example, rheumatoid arthritis, asthma, allergies, adult respiratory syndrome, organ transplantation rejection, septic shock, psoriasis, contact dermatitis, osteoporosis, osteoarthritis, tumor metastatis, diabetic retinopathy, inflammatory conditions and inflammatory bowel disease.
Treatment or prevention of the foregoing disorders is accomplished by administering a therapeutically effective amount of roxifiban to a human or animal subject in need of such treatment or prevention. The compound may be administered enterally or parenterally in solid or liquid dosage forms. In general dosages of from about 0.001 to about 10 mg/kg of body weight per day, preferably from about 0.005 to about 1 mg/kg of body weight per day are employed.
The synthesis of roxifiban and its recovery as a substantially pure crystalline product are described by Zhang et al., Tetrahedron Letters, 37(26), 4455-58 (1996); Zhang et al., J. Org. Chem., 62(8), 2469 (1997). Roxifiban has not been known previously to exist in stable crystalline polymorphic forms.
For the manufacture, purification and formulation of roxifiban, the drug advantageously is produced in a crystalline form. Accordingly, a need exists for stable crystalline forms of the drug and reliable and reproducible procedures for their manufacture.